The deregulation of mitochondria dynamics and function of the ubiquitin-proteasome system (UPS) are hallmark features of the pathogenesis of numerous neurodegenerative and aging-related disorders causing severe neurological impairment. Current therapeutic interventions that promote neuroprotection lack therapeutic efficacy. Our long-term goal is to identify targets with novel neuroprotective properties and high therapeutic efficacies that delay the onset of or cure clinical manifestations causing neurological impairment. To attain this goal we propose a research project whose long-term objective is the development of improved understanding of the role of factors controlling mitochondria dynamics and UPS functions, the identification of cross-talk processes between these factors and processes, and the effect(s) of such factors and processes in modulation of neuronal survival. Understanding the role(s) of factors that control mitochondria dynamics or UPS activity and contribute to the modulation of neuronal survival, would allow us and others to create novel value targets and therapeutic strategies to delay or cure the development of clinical manifestations leading to severe neurological impairments. We will focus on determining the functional relationships between RAN GTPase and one of its high-affinity and multi-binding targets, the RAN-binding protein 2 (RANBP2). This proposal tests our overall hypothesis that the associations between RAN GTPase and, the RAN-binding domains-2 and -3 (RBD2 and RBD3) of RANBP2, constitute a novel molecular switch to control effector domains of RANBP2 in the modulation of UPS function, mitochondria dynamics by kinesin-1, and neuronal survival. We will test this hypothesis by accomplishing the following specific aims, which focus on the mechanistic roles of RanBP2 and its RBD2 and RBD3 in the regulation of mitochondria dynamics, protein homeostasis and survival of selective neurons under normal and disease stress conditions. Aim 1. Test the hypothesis that loss-of-function of the RBD2 or RBD3 of RANBP2 promotes differential effects in mitochondria trafficking and survival among neuronal cell types. Aim 2. Test the hypothesis that loss-of-function of the RBD3 of RANBP2 promotes differential effects in UPS activity among neuronal cell types. Aim 3. Test the hypothesis that impairment of RAN GTPase-dependent modulation of mitochondria trafficking or UPS activity promotes either neuroprotection or cell death of selective neurons in three mouse models of stress-induced neurodegeneration: light-induced death of photoreceptors, high intraocular pressure-induced ganglion cell death, and MPP+induced death of dopaminergic neurons. PUBLIC HEALTH RELEVANCE: The deregulation of trafficking of mitochondria and of the machinery controlling protein degradation underlies numerous neurological disorders leading to neurodegeneration. This study seeks to identify and elucidate the role of factors, such as RanGTPase and Ran-binding protein-2, in controlling mitochondria dynamics and protein degradation and survival of various types of neurons under normal and disease stress conditions.